Skip to main content

Advertisement

Log in

Role of Interleukin-6 in Immune Complex Induced Models of Vascular Injury

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Previous studies have suggested that Interleukin-6 (IL-6) acts as a marker of vasculitis. To determine the role of IL-6 in vasculitis we utilized two models of immune complex induced vascular injury (dermal Arthus and acute pulmonary alveolitis) in IL-6 deficient (IL-6−/−) and IL-6 sufficient (IL-6+/+) mice. Plasma and bronchoalveolar lavage (BAL) levels of IL-6 were elevated in the injured IL-6+/+ mice with acute alveolitis and in the plasma of IL-6+/+ mice with dermal Arthus vasculitis. While, IL-6 levels in IL-6−/− mice were near or below the levels of detection. Histological examination of the intensity of vascular injury response demonstrated no significant differences between IL-6−/− and IL6+/+ mice. More specifically, lung permeability (total protein in the BAL) in the lung injury model in IL-6−/− mice was the same as injured IL-6+/+ mice. As a corollary, assessment of vascular permeability in both models was the same in the IL-6−/− as the IL-6+/+ mice. Quantification of leukocyte influx into the injured tissues in both models also revealed no differences between the IL-6−/− and IL-6+/+ mice. These data demonstrate that while IL-6 is upregulated in acute vascular injury it does not appear to be critical in the development of the vascular inflammatory response.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Heinrich, P. C., R. Behrmann, S. Haan, H. M. Hermanns, G. Muller-Newen, and F. Schaper. 2003. Review article. Principles of interleukin (IL)-6-type cytokine signaling and its regulation. Biochem. J. 15(374(Pt 1)):1–20.

    Article  CAS  Google Scholar 

  2. Tackey, E., P. E. Lipsky, and G. G. Illei. 2004. Rationale for interleukine-6 blockade in systemic lupus erythematosus. Lupus. 13(5):339–343.

    Article  PubMed  CAS  Google Scholar 

  3. Naka, T., N. Nishimoto, and T. Kishimoto. 2002. The paradigm of IL-6: from basic science to medicine. Arthritis Res. 4(Suppl 3):S233–S242.

    Article  PubMed  Google Scholar 

  4. Sundy, J. S., and B. F. Haynes. 2000. Cytokines and adhesion molecules in the pathogenesis of vasculitis. Curr. Rheumatol. Rep. 2(5):402–410.

    PubMed  CAS  Google Scholar 

  5. Chodorowska, G., and D. Czelej. 2003. Drug-induced hyperalergic vasculitis-activity of selected cytokines and acute phase proteins in plasma. Ann. Univ. Mariae Curie-Sklodowska Sect D, Med. 58(1):43–47.

    Google Scholar 

  6. Ohlsson, S., J. Wieslander, and M. Segelmark. 2004. Circulating cytokine profile in anti-neutrophilic cytoplasmatic autoantibody-associated vasculitis. Prediction of outcome? Mediat. Inflamm. 13(4):275–283.

    Article  CAS  Google Scholar 

  7. Nalbant, S., B. Koc, C. Top, Y. Kucukardali, Y. Baykai, M. Danaci, and I. H. Kocer. 2002. Hypersensivity vasculitis and cytokines. Rheumatol. Int. 22(6):244–248.

    Article  PubMed  CAS  Google Scholar 

  8. Goronzy, J. J., and C. M. Weyand. 2002. Cytokines in giant-cell arteritis. Review. Clevel. Clin. J Med. 69(Suppl 2):S1191–S11914.

    Google Scholar 

  9. Muller Kobold, A. C., and C. G. Kallenberg. 1999. Monocyte activation in patients with Wegener’s granulomatosis. Ann. Rheum. Dis. 58(4):237–245.

    Article  PubMed  CAS  Google Scholar 

  10. Tomer, Y., V. Barak, B. Bilburd, and Y. Shoenfeld. 1999. Cytokines in experimental autoimmune vasculitis. Evidence for a Th2 type response. Clin. Exp. Rheumatol. 17(5):521–526.

    PubMed  CAS  Google Scholar 

  11. Shanley, T. P., J. L. Foreback, D. G. Remick, T. R. Ulich, S. L. Kunkel, and P. A. Ward. 1997. Regulatory effects of interleukin-6 in immunoglobulin G immune complex-induced lung injury. Am. J. Pathol. 151(1):193–203.

    PubMed  CAS  Google Scholar 

  12. Morrow, J. D., and M. R. Opp. 2005. Diurnal variation of lipopolysaccharide-induced alterations in sleep and body temperature of interleukin-6-deficient mice. Brain Behav. Immun. 19(1):40–51.

    Article  PubMed  CAS  Google Scholar 

  13. Johnson, K. J., and P. A. Ward. 1974. Acute immunologic pulmonary alveolitis. J. Clin. Invest. 54(2):349–357.

    Article  PubMed  CAS  Google Scholar 

  14. Ward, P. A. 1965. Cochrane CG. Bound complement and immunologic injury of blood vessels. J. Exp. Med. 121:215–234.

    Article  PubMed  CAS  Google Scholar 

  15. Ward, P. A., J. S. Warren, and K. J. Johnson. 1988. Leukocytes, oxidants and tissue injury. Perspect. Crit. Care 1:69–81.

    Google Scholar 

  16. Warren, J. S., K. J. Johnson, and P. A. Ward. 1991. Immunoglobulin and complement mediated immune injury. In: The lung: scientific foundations, R. J. Crystal, J. B. West, P. J. Barnes, N. S. Cherniack and E. R. Weibel eds. Raven, New York, pp. 1939–1949.

    Google Scholar 

  17. Guo, R. F., and P. A. Ward. 2005. Role of C5a in inflammatory responses. Review. Ann. Rev. Immunol. 23:821–852.

    Article  CAS  Google Scholar 

  18. Warner, R. L., C. S. Lewis, L. Beltran, E. M. Younkin, J. Varani, and K. J. Johnson. 2001. Role of stromelysin 1 and gelatinase B in experimental acute lung injury. Am. J. Respir. Cell Mol. Biol. 24 (5):537–544.

    PubMed  CAS  Google Scholar 

  19. Warren, J. S. 1991. Disparate roles for TNF in the pathogenesis of acute immune complex alveolitis and dermal vasculitis. Clin. Immunol. Immunopathol. 61(2 Pt 1):249–259.

    PubMed  CAS  Google Scholar 

  20. Speyer, C. L., N. J. Rancilio, S. D. McClintock, J. D.Crawford, H. Gao, J. V. Sarma, and P. A. Ward. 2005. Regulatory effects of estrogen on acute lung inflammation in mice. Am. J. Physiol. Cell Physiol. 288(4):C881–C890.

    Article  PubMed  CAS  Google Scholar 

  21. Riedemann, N. C., T. A. Neff, R. F. Guo, K. D. Bernacki, I. J. Laudes, J. V. Sarma, J. D. Lambris, and P. A. Ward. 2003. Protective effects of IL-6 blockade in sepsis are linked to reduced C5a receptor expression. J. Immunol. 170(1):503–507.

    PubMed  CAS  Google Scholar 

  22. Gennari, R., and J. W. Alexander. 1995. Anti-interleukin-6 antibody treatment improves survival during gut-derived sepsis in a time-dependent manner by enhancing host defense. Crit. Care Med. 23(12):1945–1953.

    Article  PubMed  CAS  Google Scholar 

  23. Remick, D. G., G. Bolgos, S. Copeland, and J. Siddiqui. 2005. Role of interleukin-6 in mortality from and physiologic responses to sepsis. Infect. Immun. 73(5):2751–2757.

    Article  PubMed  CAS  Google Scholar 

  24. Kluger, M. J., W. Kozak, L. R. Leon, and C. A. Conn. 1998. The use of knockout mice to understand the role of cytokines in fever. Clin. Exp. Pharmacol. Physiol. 25(2):141–144.

    PubMed  CAS  Google Scholar 

  25. Sundgren-Andersson, A. K., P. Ostlund, and T. Bartfai. 1996. IL-6 is essential in TNFα induced fever. Am. J. Physiol. 275: R2028–R2034.

    Google Scholar 

  26. Johnston, R. A., I. N. Schwartzman, L. Flynt, and S. A. Shore. 2005. Role of interleukin-6 in murine airway responses to ozone. Am. J. Physiol. Lung Cell Mol. Physiol. 288(2):L390-L397.

    Article  PubMed  CAS  Google Scholar 

  27. Akira, S., H. Isshiki, T. Nakajima, S. Kinoshita, Y. Nishio, S. Natsuka, and T. Kishimoto. 1992. Regulation of expression of the interleukin 6 gene: structure and function of the transcription factor NF-IL6. Ciba Found Symp. 167:47–62.

    PubMed  CAS  Google Scholar 

  28. Kopf, M., G. Le Gros, A. J. Coyle, M. Kosco-Vilbois, and F. Brombacher. 1995. Immune responses of IL-4, IL-5, IL-6 deficient mice. Immunol. Rev. 148:45–69.

    Article  PubMed  CAS  Google Scholar 

  29. Tackey, E., P. E. Lipsky, and G. G. Illei. 2004. Rationale for interleukin-6 blockade in systemic lupus erythematosus. Lupus. 13(5):339–343.

    Article  PubMed  CAS  Google Scholar 

  30. Choy, E. 2004. Clinical experience with inhibition of interleukin-6. Rheum. Dis. Clin. North Am. 30(2):405–415.

    Article  PubMed  Google Scholar 

  31. Peterson, A. M., and B. K. Pedersen. 2005. The anti-inflammatory effect of exercise. Review. J. Appl. Physiol. 98(4):1154–1162.

    Article  Google Scholar 

  32. Gerlai, R., S. P. Williams, B. Cairns, N. Van Bruggen, P. Moran, A. Shih, I. Caras, H. Sauer, H. S. Phillips, and J. W. Winslow. 1998. Protein targeting in the analysis of learning and memory: a potential alternative to gene targeting. Exp. Brain Res. 123(1–2):24–35.

    Article  PubMed  CAS  Google Scholar 

  33. Hochgeschwender, U., and M. B. Brennan. 1995. Knock out mice rule OK. Nature 375:543.

    Article  PubMed  CAS  Google Scholar 

  34. Gerlai, R. 2001. Gene targeting: technical confounds and potential solutions in behavioral brain research. Behav. Brain Res. 125(1–2):13–21.

    Article  PubMed  CAS  Google Scholar 

  35. Routtenberg, A. 1995. Knockout mouse fault lines. Nature 374:314–315.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kent J. Johnson.

Additional information

This work is supported in part by: Pfizer Global Research & Development

Rights and permissions

Reprints and permissions

About this article

Cite this article

McClintock, S.D., Barron, A.G., Olle, E.W. et al. Role of Interleukin-6 in Immune Complex Induced Models of Vascular Injury. Inflammation 29, 154–162 (2005). https://doi.org/10.1007/s10753-006-9011-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-006-9011-1

Key words

Navigation